All cells are covered by a thick layer of carbohydrates, known as the glycocalyx, which consists of many different carbohydrate epitopes—some are cell-type specific. Cancer cells express certain unique or excessive carbohydrate structures, termed tumor-associated carbohydrate antigens (TACAs). They are important molecular targets for the development of therapeutic cancer vaccines or cancer immunotherapies, because TACAs are typically rich and exposed on the cancer cell surface and they are ideally situated for the immune system recognition and reactions. Furthermore, TACAs are widespread in malignant tissues and closely correlated with various stages of tumor progression. The goal of cancer immunotherapy is to educate the patient's immune system, either by using antibodies or by vaccination, to recognize and target the antigens uniquely expressed on cancer cells for cancer elimination.
However, a major issue associated with TACAs is that carbohydrate antigens are generally poorly immunogenic. Another issue for TACAs is that they are tolerated by the patient's immune system, because they are perceived as “self” or “normal” antigens and are not recognizable by the human immune system. Therefore, it is very difficult to use natural TACAs for the development of functional cancer vaccines.
Lipopolysaccharides (LPS), which constitute the major components on the cell surface of Gram-negative bacteria (Erridge et al., Microbes Infect. (2002), 4, 837), have been proved to be particularly endotoxic and cause septicemia. (Van Amersfoort et al., Clin. Microbiol. Rev. (2003), 16, 379). It has been further demonstrated that the LPS anchor part, namely, lipid A, is primarily responsible for the endotoxicity of LPS. Lipid A binds to Toll-like receptor 4 (TLR4) to activate a cascade of immunological responses, including the production of a number of cytokines and chemokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and interferon-β (IFN-β). (Dobrovolskaia et al., Microbes Infect. (2002), 4, 903). Thus, lipid A has become a valuable molecular template in the discovery of new immunostimulants, (Persing et al., Trends Microbiol. (2002), 10 (Suppl.), S32); Baldridge et al., in Vaccine Adjuvants (Eds.: C. J. Hackett, D. A. J. Harn), Humana Press Inc., Totowa, N.J., (2006), pp. 235), for example as a vaccine adjuvant, and in the design and development of novel conjugate vaccines. (Baldridge et al., Methods (1999), 19, 103).
In order to understand and eventually mitigate the endotoxicity of lipid A for the development of useful immunostimulant, numerous lipid A derivatives have been designed, synthesized, and biologically assayed. (Qureshi et al., Endotoxin Res. (1999), 5, 147); Morrison et al., Infect. Dis. Clin. N. Am. (1999), 13, 313); R. P. Darveau, Curr. Opin. Microbiol. (1998), 1, 36); Rietschel et al., FASEB J. (1994), 8, 217). Some examples of Lipid A molecules are denoted in Table 1 below.
TABLE 1Various Lipid A and Monophosphoryl lipid A (MPLA) molecules   E. coli lipid A    N. meningitidis lipid A    S. minnesota lipid A    K. pneumoniae lipid A    monophosphoryl E. Coli lipid A    monophosphoryl S. minnesota lipid A
It appears that the diphosphorylated hexa-acyl form of lipid A, such as Escherichia coli lipid A (Table 1), is optimally recognized by TLR4 to exhibit the full spectrum of endotoxicity (Erridge et al. (2002)). Most importantly, it was observed that the endotoxic activity of lipid A could be significantly reduced after the removal of its anomeric phosphate group, (Erridge et al., Microbes Infect. (2002), 4, 837), while its immunostimulatory property remained unaffected. For example, although Salmonella minnesota lipid A is a potent endotoxin, its 4′-O-monophosphorylated form is essentially nontoxic. (Qureshi et al., J. Biol. Chem. (1985), 260, 5271); Ribi et al., Microbiol. (1986), 9). MPLA has been proved to be clinically safe as vaccine adjuvant (Casella et al., Cell. Mol. Life Sci. (2008), 65, 3231) and even has been explored as potential vaccines against bacteria and cancer. (Baldridge et al. (1999)). Meanwhile, the special carbohydrates expressed by bacterial and cancer cells are important targets for the design and development of bacterial and cancer vaccines. (Jennings et al., Neoglycoconjugates: Preparation and Applications (Eds.: Y. C. Lee, R. T. Lee), Academic Press, San Diego, (1994), pp. 325; Danishefsky et al., Angew. Chem. Int. Ed. (2000), 39, 837). However, a major problem for carbohydrate antigens, especially the tumor-associated carbohydrate antigens (TACAs), is that they are typically poorly immunogenic. (Jennings et al. (1994). To overcome this problem, much recent effort has been focusing on synthetic multicomponent glycoconjugate vaccines, which consist of a carbohydrate antigen, an immunostimulant, and/or other functional epitopes. (Toyokuni et al., J Am Chem Soc (1994), 116, 395); Dullenkopf et al., Chem Eur J (1999), 5, 2432); Kudryashov et al., Proc Natl Acad Sci USA (2001), 98, 3264; Buskas et al., Angew Chem Int Ed Engl (2005), 44, 5985); Renaudet et al., Chem Med Chem (2008), 3, 737); Ingale et al., Chem biochem (2009), 10, 455); Bay et al., Chem Med Chem (2009), 4, 582). Therefore, there is a need in the art for methods and compounds relating to TACAs for cancer vaccines and immunotherapies.